Though current vaccines reduce the impact of influenza, IAV remains a major human pathogen with an enormous global and domestic impact, causing 30,000 deaths per year in the USA and economic costs totaling tens of billions dollars each year in the USA. Despite its remarkable impact on public health, we have only a limited understanding of the molecular mechanisms underlying its ability to evade the immune response. Antigenic drift precludes long lasting natural or vaccine induced immunity to IAV, and is the cause of yearly vaccine reformulation. Despite its remarkable impact on public health, we have only a limited understanding of the molecular mechanisms underlying antigenic drift. We found that single amino acid substitutions in the HA can escape antibody neutralization by a combination of antigenic alterations and altered specificity for host sialic acids.